Insulin like growth factor 1 (IGF1) plays an important role in brain maturation and in somatic growth. In addition, IGF1 serves as a critical mediator of sex steroid action. The objectives of this project are to elucidate IGF1's fundamental biological mechanisms of action in brain, growth plate and reproductive tissues to better understand, diagnose and treat disorders of brain development/function, growth and reproduction. The regulation of growth and reproduction has been investigated using murine and non-human primate models. It has been established that locally produced insulin-like growth factor 1 (IGF1) regulates postnatal brain growth by augmenting neuronal metabolism . Signal pathways similar to those used by insulin in the periphery are activated by IGF1 in the brain to stimulate glucose uptake, phosphorylation and incorporation into glycogen. These findings help to explain the etiology of mental retardation in individuals with genetic defects in IGF1 synthesis. Current work is aimed at elucidating the factors regulating brain IGF1 expression during development, with key fatty acids emerging as important playesrs. Study of the epiphysial growth plate in IGF1- and GHR-deficient mice have shown that IGF1 and GH act in distinct and complementary ways to enhance long bone growth. GH stimulates chondrocyte proliferation and IGF1 stimulates chondrocyte hypertrophy. Thus, the two growth factors synergistically augment the growth plate expansion, which underlies long bone growth and achievement of maximal adult stature. In our study of menopausal hormone replacement, we have found that addition of physiological androgen replacement significantly inhibits estrogen induced mammary epithelial proliferation, suggesting that combined estrogen/androgen hormone treatments may attenutae or prevent the estrogen-induced increase in breast cancer. We are now working on the mechanisms involved in the protective androgenic effects, with preliminary data suggesting that testosterone down-regulates estrogen receptor and c-myc oncogene expression and up-regulates the cell cycle inhibitor p27-kip in the mammary epithelium.